The acridine was commercially used one century ago. 3,6-Diamino acridine was used against infections in clinical practice as early as in 1913. Until 1961, acridine began its anti-tumor journey after the concept of intercalation was proposed. Acridine is one of the privileged scaffolds of antitumor drugs for two reasons: one is the linear tricyclic aromatic structure of acridine ensures it is a good DNA intercalating agent; Second, modification of acridine, such as the side chain on the pyridine ring, resulting in various biologically active compounds with different mechanisms [Belmont. P.; Constant, J. F.; Demeunynck, M. Chem. Soc. Rev., 2001, 30, 70-81]; [Martinez, R.; Chacon-Garcia, L. Curr. Med. Chem., 2005, 12, 127-151]; [Belmont, P.; Dorange, I. Expert Opin. Ther. Patents, 2008, 18, 1211-1224].
Targets of acridine compounds included topoisomerase I/II, telomerase, tubulin, ABCG2/P-gP, and protein kinase, etc. Amsacrine (m-AMSA) and DACA were among the earliest acridine compounds for anti-tumor treatment, and also two typical topoisomerase inhibitors [Lagutschenkov, A.; Dopfer, O. J. Mol. Spectrosc., 2011, 268, 66-77]; [Cholewiski, G.; Dzierzbicka, K.; Koodziejczyk, A. M. Pharm. Rep., 2011, 63, 305-336]; [Kaur, J.; Singh P. Expert Opin. Ther. Pat., 2011, 21, 437-454].
m-AMSA was used to treat leukemia in 1976, which was the first identified synthetic DNA intercalator and worked through the formation of DNA-topo II-intercalator triple complex. Now m-AMSA is used for the treatment of acute leukemia and malignant lymphoma, although shows low activity against solid tumors [Lang X. et al. Bioorg. Med. Chem. 2013, 21, 4170-4177]. DACA is topo I/topo II dual inhibitors [Crenshaw, J. M.; Graves, D. E.; Denny, W. A. Biochemistry 1995, 34, 13682-13687].
Moreover, miscellaneous dimer generated from acridine with other aromatic system via a polyamine linker would increase its affinity with DNA [Yang, X.-l.; Robinson, H.; Gao, Y.-G.; Wang, A. H. J. Biochemistry-US, 2000, 39(36), 10950-10957].
Huang and Shi et. al. disclosed a synthetic route to prepare pyrrolo[2,3,4-kl]acridin-1-(2H)-one [Wang, H.; Li, L.; Lin, W.; Xu, P.; Huang, Z.; Shi D. Org. Lett., 2012, 14, 4598-4601]. Subsequently, Wang and Ji reported the synthesis of similar compounds too [Hao, W-J.; Wang, J-Q.; Xu, X-P.; Zhang, S-L.; Wang, S-Y.; Ji, S-J. J. Org. Chem. 2013, 78, 12362-12373]. However, there were no biological activities involved.
